Chemically Atorvastatin is R—(R*,R*)]-2-(4-fluorophenyl)-β, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid. Atorvastatin is marketed as the hemi calcium salt trihydrate under the name LIPITOR by Warner Lambert Co and may be represented by Formula 1.

Atorvastatin is a member of the class of drugs called statins. Statin drugs are currently the most therapeutically effective drugs available for reducing low density lipoprotein (LDL) particle concentration in the blood stream of patients at risk for cardiovascular disease. A high level of LDL in to bloodstream has been linked to the formation of coronary lesions, which obstruct the flow of blood and can rupture and promote thrombosis; Goodman Gilman, The Pharmacological Basis of Therapeutics 879 (9th ed. 1996). Reducing plasma LDL levels has been shown to reduce the risk of clinical events in patients with cardiovascular disease and patients who are free of cardiovascular disease but who have hypercholesterolemia; Scandinavian Simvastatin Survival Study Group, 1994; Lipid Research Clinics Program, 1984a, 1984b.
U.S. Pat. No. 5,969,156 to Warner-Lambert Company, discloses crystalline Form I Atorvastatin hydrate, crystalline Form II Atorvastatin and hydrates thereof and crystalline Form IV Atorvastatin and hydrates thereof, which are useful as inhibitors of enzyme 3-hydroxy-3methylglutaryl-coenzyme A reductase (HMG-CoA reductase) and are hence useful hypolipidemic and hypocholesterolemic agents.
U.S. Pat. No. 6,121,461 also to Warner-Lambert Company, discloses crystalline Form III Atorvastatin hydrate, which is also a useful hypolipidemic and hypocholesterolemic agent.
WO 01/36384 A1 to Teva Pharmaceutical Industries Ltd discloses Form V Atorvastatin calcium and hydrates thereof; its preparation and a pharmaceutical composition thereof.
A process for the preparation of hydrated and anhydrous amorphous Atorvastatin is disclosed in U.S. Pat. No. 6,087,511 also to Warner-Lambert Company.
WO 01/28999 A1 to Egis Gyogyszergyarrt discloses a process for the preparation of amorphous Atorvastatin calcium.
It is also noteworthy to point out that U.S. Pat. No. 5,969,156 designates the Atorvastatin formed by prior art process (viz U.S. Pat. Nos. 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,280,126; 5,397,792; and 5,342,952) as amorphous Atorvastatin which has unsuitable filtration and drying characteristics for large scale production and which must be protected from light, heat, oxygen and moisture (column 1; lines 62–65).
Atorvastatin is prepared as its calcium salt, which is desirable since it enables Atorvastatin to be conveniently formulated for oral administration. There is hence a need to produce Atorvastatin calcium in a pure and crystalline form to enable formulations to meet exacting pharmaceutical requirements and specifications.
Furthermore, the process by which the crystalline form of Atorvastatin calcium is produced needs to be one, which is amenable to large-scale production. Additionally, it is desirable that the product should be in a form that is readily filterable and easily dried. Finally, it is economically desirable that the product be stable for extended periods of time without the need for specialized storage conditions.
The main aspect of the present invention is to provide novel crystalline forms of Atorvastatin calcium and hydrates thereof, and to a method for their preparation.
Another aspect of the present invention is that, the novel crystalline forms of Atorvastatin calcium and hydrates thereof are obtained in high purity. The generally preferred HPLC purity of crystalline Form VI and VII of Atorvastatin calcium and hydrates thereof, of the present invention is greater than 99.0% more preferably greater than 99.5%. Most pharmaceutical formulation processes are facilitated by use of the active materials that are free flowing high melting solids. The novel crystalline forms of Atorvastatin calcium of the present invention are high melting solids, very suited for formulation. The residual solvents associated with the novel forms, Form VI and Form VII are also very well within permissible limits and that again renders the novel crystalline forms suited for formulations.